Tygacil

Tigecycline.

Each vial contains 50 mg Tigecycline lyophilized powder, 100 mg Lactose monohydrate. The pH is adjusted with hydrochloric acid, and if necessary sodium hydroxide. The product does not contain preservatives.
Tigecycline (Tygacil) is a glycylcycline antibacterial for intravenous infusion. The chemical name of tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert-butylamino)acetamido]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.
The molecular formula is C₂₉H₃₉N₅O₈ and the molecular weight is 585.65.
Tigecycline is an orange lyophilized powder or cake.

Pharmacologic Category: Antibacterial.
Pharmacology: Pharmacodynamics: Mechanism of action: Tigecycline, a glycylcycline antibiotic, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties that transcend any known tetracycline-derivative in vitro or in vivo activity. In addition, tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has been no cross resistance observed between tigecycline and other antibiotics. In in vitro studies, no antagonism has been observed between tigecycline and other commonly used antibiotics. In general, tigecycline is considered bacteriostatic. At 4 times the minimum inhibitory concentration (MIC), a 2-log reduction in colony counts was observed with tigecycline against Enterococcus spp., Staphylococcus aureus, and Escherichia coli. However, tigecycline has shown some bactericidal activity, and a 3-log reduction was observed against Neisseria gonorrhoeae. Tigecycline has also demonstrated bactericidal activity against common respiratory strains of Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila.
Susceptibility Test Methods: Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure based on dilution methods (broth, agar, or microdilution) or equivalent using standardized inoculum and concentrations of tigecycline. For broth dilution tests for aerobic organisms, MICs must be determined in testing medium that is fresh (<12 hours old). The MIC values should be interpreted according to the criteria provided in Table 1.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 μg tigecycline to test the susceptibility of microorganisms to tigecycline. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tigecycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 μg tigecycline disk should be interpreted according to the criteria in Table 1. (See Table 1.)

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A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.
Quality Control: As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standard tigecycline powder should provide the MIC values provided in Table 2. For the diffusion technique using the 15 μg tigecycline disk, laboratories should use the criteria provided in Table 2 to test quality control strains. (See Table 2.)

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The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. The information as follows provides only approximate guidance on the probability as to whether the microorganism will be susceptible to tigecycline or not: Susceptible: Gram-positive aerobes: Enterococcus avium, Enterococcus casseliflavus, Enterococcus faecalis* (includes vancomycin-susceptible strains), Enterococcus faecalis (includes vancomycin-resistant strains), Enterococcus faecium (includes vancomycin-susceptible and -resistant strains), Enterococcus gallinarum, Listeria monocytogenes, Staphylococcus aureus* (includes methicillin-susceptible and -resistant strains, including isolates that bear molecular and virulence markers commonly associated with community-acquired MRSA including the SCCmec type IV element and the pvl gene), Staphylococcus epidermidis (includes methicillin-susceptible and -resistant strains), Staphylococcus haemolyticus, Streptococcus agalactiae*, Streptococcus anginosus* (includes S. anginosus, S. intermedius, S. constellatus), Streptococcus pyogenes*, Streptococcus pneumoniae* (penicillin-susceptible isolates), Streptococcus pneumoniae (penicillin-resistant isolates), Viridans group streptococci.
Gram-negative aerobes: Acinetobacter calcoaceticus/baumannii complex, Aeromonas hydrophila, Citrobacter freundii*, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae*, Escherichia coli* (including extended spectrum beta lactamase-producing strains), Haemophilus influenzae*, Haemophilus parainfluenzae, Klebsiella oxytoca*, Klebsiella pneumoniae* (including extended spectrum beta lactamase-producing strains), Klebsiella pneumoniae (including AmpC producing strains), Legionella pneumophila*, Moraxella catarrhalis*, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Salmonella enterica ser. Enteritidis, Salmonella enterica ser. Paratyphi, Salmonella entericaser. Typhi, Salmonella enterica ser. Typhimurium, Serratia marcescens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Stenotrophomonas maltophilia.
Anaerobic bacteria: Bacteroides fragilis*, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron*, Bacteroides uniformis*, Bacteroides vulgatus*, Clostridium difficile, Clostridium perfringens*, Peptostreptococcus spp., Peptostreptococcus micros*, Porphyromonas spp., Prevotella spp.
Atypical bacteria: Chlamydia pneumoniae*, Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycoplasma pneumoniae*.
*Clinical efficacy has been demonstrated for susceptible isolates in the approved clinical indications.
Resistant: Gram-negative aerobes: Pseudomonas aeruginosa.
Anaerobic bacteria: No naturally-occurring species have been found to be inherently resistant to tigecycline.
Resistance: There has been no cross-resistance observed between tigecycline and other antibiotics.
Tigecycline is able to overcome the two major tetracycline resistance mechanisms, ribosomal protection and efflux.
In in vitro studies, no antagonism has been observed between tigecycline and any other commonly used antibiotic class.
Clinical trial data on efficacy: Complicated Skin and Skin Structure Infections (cSSSI): Tigecycline was evaluated in adults for the treatment of cSSSI in two randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with vancomycin (1 g IV every 12 hours)/aztreonam (2 g IV every 12 hours) for 5 to 14 days. Subjects with complicated deep soft-tissue infections, including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) subjects. (See Table 3.)

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Clinical cure rates at TOC by pathogen in microbiologically evaluable (ME) subjects with cSSSI are presented in Table 4. (See Table 4.)

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Tigecycline did not meet non-inferiority criteria in comparison with ertapenem in a study of subjects with diabetic foot infection (See Table 5). This was a randomized, double-blind, multinational, multicenter trial comparing tigecycline (150 mg every 24 hours) with ertapenem (1 g every 24 hours, with or without vancomycin) for up to 28 days. The primary efficacy endpoint was the clinical response at the TOC assessment in the co-primary CE and c-mITT populations. The non-inferiority margin was -10% for the difference in cure rates between the 2 treatments. (See Table 5.)

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Complicated Intra-abdominal Infections (cIAI): Tigecycline was evaluated in adults for the treatment of cIAI in two randomized, double-blind, active-controlled, multinational, multicenter studies. These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg IV every 6 hours) for 5 to 14 days. Subjects with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of the intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the ME and the microbiologic modified intent-to-treat (m-mITT) subjects. (See Table 6.)

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Clinical cure rates at TOC by pathogen in ME subjects with cIAI are presented in Table 7. (See Table 7.)

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Community-Acquired Pneumonia (CAP): Tigecycline was evaluated in adults for the treatment of CAP in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 308 and 313). These studies compared tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg IV every 12 or 24 hours). In one study (Study 308), after at least 3 days of IV therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Subjects with CAP who required hospitalization and IV therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit in the co-primary populations of the CE and c-mITT subjects. See Table 8. Clinical cure rates at TOC by pathogen in the ME subjects are presented in Table 9. (See Tables 8 and 9.)

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Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE) spp.: Tigecycline was evaluated in adults for the treatment of various serious infections (cIAI, cSSSI, and other infections) due to VRE and MRSA in Study 307.
Study 307 was a randomized, double-blind, active-controlled, multinational, multicenter study evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) and vancomycin (1 g IV every 12 hours) for the treatment of infections due to MRSA and evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) and linezolid (600 mg IV every 12 hours) for the treatment of infections due to VRE for 7 to 28 days. Subjects with cIAI, cSSSI, and other infections were enrolled in this study. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the ME and the m-mITT subjects. For clinical cure rates, see Table 10 for MRSA and Table 11 for VRE. (See Tables 10 and 11.)

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Resistant Gram-negative Pathogens: Tigecycline was evaluated in adults for the treatment of various serious infections (cIAI, cSSSI, CAP, and other infections) due to resistant gram-negative pathogens in Study 309.
Study 309 was an open-label, multinational, multicenter study evaluating tigecycline (100 mg IV initial dose followed by 50 mg every 12 hours) for the treatment of infections due to resistant gram-negative pathogens for 7 to 28 days. Subjects with cIAI, cSSSI, CAP, and other infections were enrolled in this study. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the ME and the m-mITT subjects. (See Table 12.)

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Rapidly Growing Mycobacterial Infections: In uncontrolled clinical studies and compassionate-use experience from 8 countries, 52 subjects with rapidly-growing mycobacterial infections (most frequently M. abscessus lung disease) were treated with tigecycline, along with other antibiotics. The mean and median durations of treatment were approximately 5½ months and 3 months, respectively (range: 3 days to approximately 3½ years). Approximately half of the subjects achieved clinical improvement (i.e., improvement in signs and symptoms of lung disease, or healing of wound, skin lesions, or nodules in disseminated disease). Approximately half of the subjects required dose reductions or discontinued treatment due to nausea, vomiting, or anorexia.
Pediatric population: In an open-label, ascending multiple-dose study, 39 children aged 8 to 11 years with cIAI or cSSSI were administered tigecycline (0.75, 1, or 1.25 mg/kg). All patients received IV tigecycline for a minimum of 3 consecutive days to a maximum of 14 consecutive days, with the option to be switched to an oral antibiotic on or after day 4.
Clinical cure was assessed between 10 and 21 days after the administration of the last dose of treatment. The summary of clinical response in the modified intent-to-treat (mITT) population results is shown in following table. (See Table 13.)

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Efficacy data shown previously should be viewed with caution as concomitant antibiotics were allowed in this study. In addition, the small number of patients should also be taken into consideration.
Cardiac Electrophysiology: No significant effect of a single intravenous dose of tigecycline 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.
Pharmacokinetics: The mean pharmacokinetic parameters of tigecycline for the recommended dosage regimen after single and multiple intravenous doses are summarized in Table 14.
Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes. (See Table 14.)

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Absorption: Tigecycline is administered intravenously, and therefore has 100% bioavailability.
Distribution: The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 μg/mL). Animal and human pharmacokinetic studies have demonstrated that tigecycline readily distributes to tissues. In rats receiving a single or multiple doses of C-tigecycline, radioactivity was well distributed to most tissues, with the highest overall exposure observed in bone, bone marrow, thyroid gland, kidney, spleen, and salivary gland. In humans, the steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume and into the tissues of humans.
Two studies examined the steady-state pharmacokinetic profile of tigecycline in specific tissues or fluids of healthy subjects receiving tigecycline 100 mg followed by 50 mg every 12 hours. In a bronchoalveolar lavage study, the tigecycline AUC_0-12h (134 μg•h/mL) in alveolar cells was approximately 77.5-fold higher than the AUC_0-12h in the serum of these subjects, and the AUC_0-12h (2.28 μg•h/mL) in epithelial lining fluid was approximately 32% higher than the AUC_0-12h in serum. In a skin blister study, the AUC_0-12h (1.61 μg•hr/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC_0-12h in the serum of these subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Tissue concentrations at 4 hours after tigecycline administration were measured in the following tissue and fluid samples: gallbladder, lung, colon, synovial fluid, and bone. Tigecycline attained higher concentrations in tissues versus serum in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6). The concentration of tigecycline in these tissues after multiple doses has not been studied.
Metabolism: Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving ¹⁴C-tigecycline, tigecycline was the primary ¹⁴C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.
Elimination: The recovery of total radioactivity in feces and urine following administration of ¹⁴C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
Tigecycline is a substrate of P-gp based on an in vitro study using a cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known.
Special populations: Hepatic insufficiency: In a study comparing 10 subjects with mild hepatic impairment (Child Pugh A), 10 subjects with moderate hepatic impairment (Child Pugh B), and five subjects with severe hepatic impairment (Child Pugh C) to 23 age- and weight-matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in subjects with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25%, and the half-life of tigecycline was prolonged by 23% in subjects with moderate hepatic impairment (Child Pugh B). In addition, systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in subjects with severe hepatic impairment (Child Pugh C).
Based on the pharmacokinetic profile of tigecycline, no dosage adjustment is warranted in subjects (including pediatrics) with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). However, in subjects with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be reduced by 50%. Adult dose should be altered to 100 mg followed by 25 mg every 12 hours. Subjects with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Dosage & Administration).
Renal insufficiency: A single-dose study compared 6 subjects with severe renal impairment (creatinine clearance ClCr ≤30 mL/min), 4 end stage renal disease subjects receiving tigecycline 2 hours before hemodialysis, 4 end stage renal disease subjects receiving tigecycline after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not altered in any of the renally-impaired subject groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in subjects with renal impairment or in subjects undergoing hemodialysis (see Dosage & Administration).
Elderly: No overall differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65-75; n=13, age 75, and younger subjects (n=18) receiving a single, 100 mg dose of tigecycline. Therefore, no dosage adjustment is necessary based on age.
Children: Tigecycline pharmacokinetics were investigated in two studies. The first study enrolled children aged 8-16 years (n=24) who received single doses of tigecycline (0.5, 1, or 2 mg/kg, up to a maximum dose of 50 mg, 100 mg, and 150 mg, respectively) administered intravenously over 30 minutes. The second study was performed in children aged 8 to 11 years who received multiple doses of tigecycline (0.75, 1, or 1.25 mg/kg up to a maximum dose of 50 mg) every 12 hours administered intravenously over 30 minutes. No loading dose was administered in these studies. Pharmacokinetic parameters are summarised in the table as follows. (See Table 15.)

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The target AUC_0-12h in adults after the recommended dose of 100 mg loading and 50 mg every 12 hours, was approximately 2500 ng•h/mL.
Population PK analysis of both studies identified body weight as a covariate of tigecycline clearance in children aged 8 years and older. A dosing regimen of 1.2 mg/kg of tigecycline every 12 hours (to a maximum dose of 50 mg every 12 hours) for children aged 8 to <12 years, and of 50 mg every 12 hours for adolescents aged 12 to <18 years would likely result in exposures comparable to those observed in adults treated with the approved dosing regimen.
Gender: In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.
Race: In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as "other" participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), Black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and "other" subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.
Toxicology: Preclinical Safety Data: Carcinogenicity: Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline.
Mutagenicity: No mutagenic or clastogenic potential was found in a battery of tests, including an in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo micronucleus assay.
Impairment of fertility: Tigecycline did not affect mating or fertility in rats at exposures up to 4.7 times the human daily dose based on AUC. In female rats, there were no compound-related effects on ovaries or estrus cycles at exposures up to 4.7 times the human daily dose based on AUC.
Other: Decreased erythrocytes, reticulocytes, leukocytes and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8.1 times and 9.8 times the human daily dose based on AUC in rats and dogs, respectively. These alterations were shown to be reversible after two weeks of dosing.
Bolus intravenous administration of tigecycline has been associated with a histamine response in preclinical studies. These effects were observed at exposures of 14.3 and 2.8 times the human daily dose based on the AUC in rats and dogs, respectively.
No evidence of photosensitivity was observed in rats following administration of tigecycline.

Adults: Tigecycline is indicated for treatment of the following infections in adults: Complicated skin and skin structure infections (cSSSI), including those with methicillin-resistant Staphylococcus aureus (MRSA): Tigecycline is not indicated for the treatment of diabetic foot infections (DFI) (see Pharmacology: Pharmacodynamics under Actions).
Complicated intra-abdominal infections (cIAI).
Community-acquired pneumonia (CAP): Tigecycline is not indicated for the treatment of hospital-acquired or ventilator-associated pneumonia (see Precautions).
Pediatrics: Tigecycline is indicated in children from the age of eight years for treatment of the following infections only in situations where other alternative antibiotics are not suitable: Complicated skin and skin structure infections (cSSSI), including those with methicillin-resistant Staphylococcus aureus (MRSA): Tigecycline is not indicated for the treatment of diabetic foot infections (DFI) (see Pharmacology: Pharmacodynamics under Actions).
Complicated intra-abdominal infections (cIAI).

The recommended dosage regimen for adults for tigecycline is an initial dose of 100 mg, followed by 50 mg every 12 hours. Intravenous (IV) infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
The recommended duration of treatment with tigecycline for cSSSI or for cIAI is 5 to 14 days. The recommended duration of treatment with tigecycline for CAP is 7 to 14 days. The duration of therapy should be guided by the severity and site of the infection and the patient's clinical and bacteriological progress.
Use in patients with renal impairment: No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing hemodialysis (see Pharmacology: Pharmacokinetics under Actions).
Use in patients with hepatic impairment: No dosage adjustment is necessary in patients (including pediatrics) with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Based on the pharmacokinetic profile of tigecycline in patients with severe hepatic impairment (Child Pugh C), the dose of tigecycline should be reduced by 50%. Adult dose should be altered to 100 mg followed by 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response (see Pharmacology: Pharmacokinetics under Actions).
Use in children: Tigecycline is only to be used to treat patients aged 8 years and older after consultation with a physician with appropriate experience in the management of infectious diseases. Tigecycline should not be used in children under 8 years of age due to the lack of data on safety and efficacy in this age group and because of teeth discoloration (see Precautions).
Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of tigecycline every 12 hours intravenously to a maximum dose of 50 mg of tigecycline every 12 hours.
Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline every 12 hours.
Intravenous (IV) infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
The proposed pediatric doses of tigecycline were chosen based on exposures observed in pharmacokinetic trials, which included small numbers of pediatric patients (see Pharmacology: Pharmacokinetics under Actions).
Use in elderly: In a pooled analysis of 3900 subjects who received tigecycline in Phase 3 and 4 clinical studies, 1026 were 65 years and over. Of these, 419 were 75 years and over. No unexpected overall differences in safety were observed between these subjects and younger subjects. No dosage adjustment is necessary in elderly patients.
Race and gender: No dosage adjustment is necessary based on race or gender (see Pharmacology: Pharmacokinetics under Actions).
Mode of administration: Intravenous infusion.

No specific information is available on the treatment of overdose with tigecycline. Intravenous administration of tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose IV toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD₅₀) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD₅₀ was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.

Tigecycline is contraindicated for use in patients who have known hypersensitivity to tigecycline.

An increase in all-cause mortality has been observed across Phase 3 and 4 clinical trials in tigecycline treated subjects versus comparator-treated subjects. In a pooled analysis of all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of subjects receiving tigecycline and 3.0% (110/3646) of subjects receiving comparator drugs resulting in an unadjusted risk difference of 0.9% (95% CI 0.1, 1.8). In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline and comparator-treated subjects. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting among treatment options (see Adverse Reactions).
Anaphylactic reaction/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening.
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics. Therefore, tigecycline should be administered with caution in patients with known hypersensitivity to tetracycline class antibiotics.
Results of studies in rats with tigecycline have shown bone discoloration. Tigecycline may be associated with permanent tooth discoloration in humans during tooth development.
Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent.
Caution should be exercised when considering tigecycline monotherapy in patients with cIAI secondary to clinically apparent intestinal perforation. In Phase 3 and 4 cIAI studies (n=2775), 140/1382 tigecycline-treated subjects and 142/1393 comparator-treated subjects presented with intestinal perforations. Of these subjects, 8/140 subjects treated with tigecycline and 8/142 subjects treated with comparator developed sepsis/septic shock. The relationship of this outcome to treatment cannot be established.
Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline.
Glycylcycline class antibiotics are structurally similar to tetracycline class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia).
Pancreatitis acute, which can be fatal, has occurred (frequency: uncommon) in association with tigecycline treatment (see Adverse Reactions). The diagnosis of pancreatitis acute should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of pancreatitis acute. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in patients suspected of having developed pancreatitis.
Monitoring of blood coagulation parameters, including blood fibrinogen, is recommended prior to treatment initiation with tigecycline and regularly while on treatment (see Adverse Reactions).
The safety and efficacy of tigecycline in patients with hospital acquired pneumonia (HAP) have not been established. In a study of subjects with HAP, subjects were randomized to receive tigecycline (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, subjects were allowed to receive specified adjunctive therapies. The subgroup of subjects with ventilator-associated pneumonia (VAP) who received tigecycline had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (25/131 [19.1%] versus 15/122 [12.3%]) than the comparator. Of those subjects with VAP and bacteremia at baseline, those who received tigecycline had greater mortality (9/18 [50.0%] versus 1/13 [7.7%]) than the comparator.
As with other antibiotic preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.
Abuse and dependence: Drug abuse and dependence have not been demonstrated and are unlikely.
Effects on ability to drive and use machines: Tigecycline can cause dizziness (see Adverse Reactions), which may impair the ability to drive and/or operate machinery.
Use in Children: Clinical experience in the use of tigecycline for the treatment of infections in pediatric patients aged 8 years and older is very limited (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions). Consequently, use in children should be restricted to those clinical situations where no alternative antibacterial therapy is available.
Nausea and vomiting are very common adverse reactions in children and adolescents (see Adverse Reactions). Attention should be paid to possible dehydration.
Abdominal pain is commonly reported in children as it is in adults. Abdominal pain may be indicative of pancreatitis. If pancreatitis develops, treatment with tigecycline should be discontinued.
Liver function tests, coagulation parameters, hematology parameters, amylase and lipase should be monitored prior to treatment initiation with tigecycline and regularly while on treatment.
Tigecycline should not be used in children under 8 years of age due to the lack of safety and efficacy data in this age group and because tigecycline may be associated with permanent teeth discoloration (see Dosage & Administration and Adverse Reactions).

Pregnancy: Tigecycline may cause fetal harm when administered to a pregnant woman. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline.
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, ¹⁴C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 4.7 times and 1.1 times the human daily dose based on AUC in rats and rabbits, respectively. An increased incidence of fetal loss was observed at exposures of 1.1 times the human daily dose based on AUC in rabbits, at dosages producing minimal maternal toxicity.
There are no adequate and well-controlled studies of tigecycline in pregnant women. Tigecycline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Tigecycline has not been studied for use during labor and delivery.
Lactation: Results from animal studies using ¹⁴C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in the nursing pups as a result of exposure via the maternal milk.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tigecycline is administered to a nursing woman (see Dosage & Administration).

Expected frequency of adverse reactions is presented in CIOMS frequency categories: Very Common: ≥10%; Common: ≥1% and <10%; Uncommon: ≥0.1% and <1%; Rare: ≥0.01% and <0.1%; Very Rare: <0.01%; Frequency not known: cannot be estimated from the available data.
For patients who received tigecycline, the following adverse reactions were reported: See Table 16.

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In a pooled analysis of all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of subjects receiving tigecycline and 3.0% (110/3646) of subjects receiving comparator drugs. In a pooled analysis of these trials, the risk difference of all-cause mortality was 0.9% (95% CI 0.1, 1.8) between tigecycline and comparator-treated subjects. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline-treated and comparator-treated subjects. No significant differences were observed between tigecycline and comparators within each infection type (see Table 17). The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, or complications of infection or underlying co-morbidities. (See Table 17.)

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The most common treatment-emergent adverse reactions in subjects treated with tigecycline were nausea 29.9% (19.3% mild; 9.2% moderate; 1.4% severe) and vomiting 19.9% (12.1% mild; 6.8% moderate; 1.1% severe). In general, nausea or vomiting occurred early (Days 1-2).
Discontinuation from tigecycline was most frequently associated with nausea (1.6%) and vomiting (1.3%).
Pediatric population: Very limited safety data were available from two PK studies (see Pharmacology: Pharmacokinetics under Actions). No new or unexpected safety concerns were observed with tigecycline in these studies.
In an open-label, single ascending dose PK study, the safety of tigecycline was investigated in 25 children aged 8 to 16 years who recently recovered from infections. The adverse reaction profile of tigecycline in these 25 subjects was generally consistent with that in adults.
The safety of tigecycline was also investigated in an open-label, ascending multi-dose PK study in 58 children aged 8 to 11 years with cSSSI (n=15), cIAI (n=24) or community-acquired pneumonia (n=19). The adverse reaction profile of tigecycline in these 58 subjects was generally consistent with that in adults, with the exception of nausea (48.3%), vomiting (46.6%) and elevated lipase in serum (6.9%) which were seen at greater frequencies in children than in adults.

Tigecycline (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg every 24 hours) were coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the C_max of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in C_max did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment is necessary when tigecycline is administered with digoxin.
Concomitant administration of tigecycline (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single dose) to healthy subjects resulted in a decrease in clearance of R-warfarin and S-warfarin by 40% and 23%, and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on increased international normalized ratio (INR). In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.
In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome CYP450 isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, tigecycline is not expected to alter the metabolism of drugs metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.
In vitro studies using Caco-2 cells indicate that tigecycline does not inhibit digoxin flux, suggesting that tigecycline is not a P-glycoprotein (P-gp) inhibitor. This in vitro information is consistent with the lack of effect of tigecycline on digoxin clearance noted in the in vivo drug interaction study described previously.
Tigecycline is a substrate of P-gp based on an in vitro study using a cell line overexpressing P-gp. The potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known. Coadministration of P-gp inhibitors (e.g., ketoconazole or cyclosporine) or P-gp inducers (e.g., rifampicin) could affect the pharmacokinetics of tigecycline.
Concurrent use of antibiotics with oral contraceptives may render oral contraceptives less effective.
Concomitant use of tigecycline and calcineurin inhibitors such as tacrolimus or cyclosporine may lead to an increase in serum trough concentrations of the calcineurin inhibitors. Therefore, serum concentrations of the calcineurin inhibitor should be monitored during treatment with tigecycline to avoid drug toxicity.
Interference with laboratory and other diagnostic tests: There are no reported drug-laboratory test interactions.

Incompatibilities: Tigecycline Lactose Formulation: Compatible intravenous solutions include 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, and Lactated Ringer's Injection, USP.
Tigecycline is compatible with the following drugs or diluents when used with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP and administered simultaneously through the same line: amikacin, dobutamine, dopamine HCl, gentamicin, haloperidol, Lactated Ringer's, lidocaine HCl, metoclopramide, morphine, norepinephrine, piperacillin/tazobactam (EDTA formulation), potassium chloride, propofol, ranitidine HCl, theophylline, and tobramycin.
The following drugs should not be administered simultaneously through the same line as tigecycline: amphotericin B, amphotericin B lipid complex, diazepam, esomeprazole and omeprazole.
Special precautions for disposal and other handling: The lyophilized powder should be reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, or Lactated Ringer's Injection, USP, to achieve a concentration of 10 mg/mL of tigecycline. The vial should be gently swirled until the drug dissolves. Withdraw 5 mL of the reconstituted solution from the vial and add to a 100 mL IV bag for infusion. For a 100 mg dose, reconstitute using two vials into a 100 mL IV bag. (Note: The vial contains a 6% overage. Thus, 5 mL of reconstituted solution is equivalent to 50 mg of the drug.) The reconstituted solution should be yellow to orange in color; if not, the solution should be discarded. Parenteral drug products should be inspected visually for particulate matter and discoloration (e.g., green or black) prior to administration whenever solution and container permit.
Tigecycline may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of tigecycline with either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Injection should be made with an infusion solution compatible with tigecycline and with any other drug(s) administered via this common line (see Incompatibilities as previously mentioned).
Reconstituted solution must be transferred and further diluted for IV infusion.

Tigecycline should be stored at temperatures not exceeding 30°C prior to reconstitution.
Once reconstituted, tigecycline may be stored at room temperature (not to exceed 25°C/77°F) for up to 24 hours (up to 6 hours in the vial and the remaining time in the IV bag). Alternatively, tigecycline mixed with 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for up to 48 hours following immediate transfer of the reconstituted solution into the IV bag.
If the storage conditions exceed 25°C/77°F after reconstitution, tigecycline should be used immediately.

Tetracyclines

J01AA12 - tigecycline ; Belongs to the class of tetracyclines. Used in the systemic treatment of infections.

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